Abstract

Acetaminophen (APAP) intoxication has been shown to activate Kupffer cells. Kupffer cell activation is also associated with the release of proinflammatory cytokines which can induce a variety of pathophysiological responses. These studies examined whether proinflammatory cytokines are produced in response to a hepatotoxic dose of APAP, and if so, the role they play in the observed pathological response. Female B6C3F1 mice received 500 mg APAP/kg in the presence and absence of antibodies against tumor necrosis factor-α (TNF-α), interleukin-1-α (IL-1α), and IL-1 receptor antagonist (IL-1ra). Serum TNF-α, IL-1α, and liver-associated enzyme levels were measured. In addition, the levels of mRNA transcripts for IL-1α, IL-6, and TNF-α from livers of treated mice were examined by reverse transcription-polymerase chain reaction (RT-PCR). Administration of APAP resulted in an immediate reduction in body temperature as well as elevated serum levels of IL-1α and TNF-α that reached a peak at 12 and 16 hr, respectively. The reduction in body temperature was partially blocked by injection of antibodies against TNF-α or IL-1α. Furthermore, neutralization of TNF-α delayed the increase in serum IL-1α and liver enzyme levels. In contrast, pretreatment with IL-1ra antisera exacerbated the effect of APAP on body temperature and increased the release of liver enzymes. These data suggest that TNF-α and IL-1α are released in response to APAP intoxication and are responsible for certain pathological manifestations of APAP-induced hepatotoxicity.

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